This invention is directed to substituted xcex2-alanines, their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states capable of being modulated by the inhibition of cell adhesion.
Cell adhesion is a process by which cells associate with each other, migrate towards a specific target or localise within the extra-cellular matrix. Many of the cell-cell and cell-extracellular matrix interactions are mediated by protein ligands (e.g. fibronectin, vitronectin and VCAM-1) and their integrin receptors [e.g. VLA-4 (xcex14xcex21)]. Recent studies have shown these interactions to play an important part in many physiological (e.g. embryonic development and wound healing) and pathological conditions (e.g. tumour-cell invasion and metastasis, inflammation, atherosclerosis and autoimmune disease).
A wide variety of proteins serve as ligands for integrin receptors. In general, the proteins recognised by integrins fall into one of three classes: extracellular matrix proteins, plasma proteins and cell surface proteins. Extracellular matrix proteins such as collagen fibronectin, fibrinogen, laminin, thrombospondin and vitronectin bind to a number of integrins. Many of the adhesive proteins also circulate in plasma and bind to activated blood cells. Additional components in plasma that are ligands for integrins include fibrinogen and factor X. Cell bound complement C3bi and several transmembrane proteins, such as Ig-like cell adhesion molecule (ICAM-1,2,3) and vascular cell adhesion molecule (VCAM-1), which are members of the Ig superfamily, also serve as cell-surface ligands for some integrins.
Integrins are heterodimeric cell surface receptors consisting of two subunits called xcex1 and xcex2. There are at least twelve different xcex1-subunits (xcex11-xcex16, xcex1-L, xcex1-M, xcex1-X, xcex1-IIb, xcex1-V and xcex1-E) and at least nine different xcex2 (xcex21-xcex29) subunits. The integrin family can be subdivided into classes based on the xcex2 subunits, which can be associated with one or more xcex1-subunits. The most widely distributed integrins belong to the xcex21 class, also known as the very late antigens (VLA). The second class of integrins are leukocyte specific receptors and consist of one of three xcex1-subunits (xcex1-L, xcex1-M or xcex1-X) complexed with the xcex22 protein. The cytoadhesins xcex1-IIbxcex23 and xcex1-Vxcex23, constitute the third class of integrins.
The present invention principally relates to agents which modulate the interaction of the ligand VCAM-1 with its integrin receptor xcex14xcex21 (VLA-4), which is expressed on numerous hematopoietic cells and established cell lines, including hematopoietic precursors, preipheral and cytotoxic T lymphocytes, B lymphocytes, monocytes, thymocytes and eosinophils.
The integrin xcex14xcex21 mediates both cell-cell and cell-matrix interactions. Cells expressing xcex14xcex21 bind to the carboxy-terminal cell binding domain of the extracellular matrix protein fibronectin, to the cytokine-inducible endothelial cell surface protein VCAM-1, and to each other to promote homotypic aggregation. The expression of VCAM-1 by endothelial cells is upregulated by proinflammatory cytokines such as INF-xcex3, TNF-xcex1 and LI-1xcex2.
Regulation of xcex14xcex21 mediated cell adhesion is important in numerous physiological processes, including T-cell proliferation, B-cell localisation to germinal centres, and adhesion of activated T-cells and eosinophils to endothelial cells. Evidence for the involvement of VLA4/VCAM-1 interaction in various disease processes such as melanoma cell division in metastasis, T-cell infiltration of synovial membranes in rheumatoid arthritis, autoimmune diabetes, collitis and leukocyte penetration of the blood-brain barrier in experimental autoimmune encephalomyelitis, atherosclerosis, peripheral vascular disease, cardiovascular disease and multiple sclerosis, has been accumulated by investigating the role of the peptide CS-1 (the variable region of fibronectin to which xcex14xcex21 binds via the sequence Leu-Asp-Val) and antibodies specific for VLA-4 or VCAM-1 in various in vitro and in vivo experimental models of inflammation. For example, in a Streptococcal cell wall-induced experimental model of arthritis in rats, intravenous administration of CS-1 at the initiation of arthritis suppresses both acute and chronic inflammation (S. M. Wahl et al., J. Clin. Invest., 1994, 24, pages 655-662). In the oxazalone-sensitised model of inflammation (contact hypersensitivity response) in mice, intravenous administration of anti-xcex14 specific monoclonal antibodies significantly inhibited (50-60% reduction in the ear swelling response) the efferent response (P. L. Chisholm et al. J. Immunol., 1993, 23, pages 682-688).
We have now found a novel group of substituted xcex2-alanines which have valuable pharmaceutical properties, in particular the ability to regulate the interaction of VCAM-1 and fibronectin with the integrin VLA-4 (xcex14xcex21).
Thus, in one aspect, the present invention is directed to compounds of general formula (I): 
wherein:
R1 is hydrogen, halogen, lower alkyl or lower alkoxy;
X1, X2 and X6 independently represent N or CR2; and
one of X3, X4 and X5 represents CR3 and the others independently represents N or CR2 
[where R2 is hydrogen, halogen, lower alkyl or lower alkoxy; and R3 represents a group xe2x80x94L1xe2x80x94(CH2)nxe2x80x94C(xe2x95x90O)xe2x80x94N(R4)xe2x80x94CH2xe2x80x94CH2xe2x80x94Y in which:
R4 is aryl or heteroaryl, or R4 is alkyl, alkenyl, alkynyl each optionally substituted by one or more groups chosen from halo, oxo, R5, xe2x80x94C(xe2x95x90O)xe2x80x94R7, xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94R7or xe2x80x94C(xe2x95x90O)NY1Y2, or R4 is cycloalkenyl, cycloalkyl or heterocycloalkyl each optionally substituted by one or more groups chosen from oxo, R6 or xe2x80x94L2xe2x80x94R6 {where R5 is an acidic functional group (or corresponding protected derivative), aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, xe2x80x94ZR7 or xe2x80x94NY1Y2; R6 is an acidic functional group (or corresponding protected derivative), aryl, heteroaryl, heterocycloalkyl, xe2x80x94ZH, xe2x80x94Z1R7 or xe2x80x94NY1Y2; R7 is alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; L2 is alkylene; Y1 and Y2 are independently hydrogen, acyl, alkyl [optionally substituted by hydroxy, heterocycloalkyl, or one or more carboxy or xe2x80x94C(xe2x95x90O)xe2x80x94NHR8 groups (where R8 is hydrogen or lower alkyl)], alkylsulphonyl, aryl, arylalkyloxycarbonyl, arylsulphonyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; or the group xe2x80x94NY1Y2 may form a 5-7 membered cyclic amine which (i) may be optionally substituted with one or more substituents selected from carboxamido, carboxy, hydroxy, oxo, hydroxyalkyl, HOCH2CH2xe2x80x94(OCH2CH2)mxe2x80x94 (where m is zero, or an integer one or two), or alkyl optionally substituted by carboxy or carboxamido (ii) may also contain a further heteroatom selected from O, N, S or SO2 and (iii) may also be fused to additional aromatic, licteroaromatic, heterocycloalkyl or cycloalkyl rings to form a bicyclic or tricyclic ring system; Z is O or S; and Z1 is O or S(O)m};
L1 represents a xe2x80x94R9xe2x80x94R10xe2x80x94 linkage, in which R9 is a straight or branched C1-6alkylene chain, a straight or branched C2-6alkenylene chain or a straight or branched C2-6alkynylene chain, and R10 is a direct bond, cycloalkylene, heterocycloalkylene, arylene, heteroaryidiyl, xe2x80x94C(xe2x95x90Z)xe2x80x94NR11xe2x80x94, xe2x80x94NR11xe2x80x94C(xe2x95x90Z)xe2x80x94, xe2x80x94Z1, xe2x80x94NR11xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90NOR11)xe2x80x94, xe2x80x94NR11xe2x80x94C(xe2x95x90Z)xe2x80x94NR11xe2x80x94, xe2x80x94SO2xe2x80x94NR11xe2x80x94, xe2x80x94NR11xe2x80x94SO2xe2x80x94, xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94NR11xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94NR11xe2x80x94 (where R11 is a hydrogen atom or R4); but excluding compounds where an oxygen, nitrogen or sulphur atom is attached directly to a carbon carbon multiple bond;
Y is carboxy (or an acid bioisostere) or xe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2; and n is an integer from 1 to 6];
and their prodrugs, and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their prodrugs.
In the present specification, the term xe2x80x9ccompounds of the inventionxe2x80x9d, and equivalent expressions, are meant to embrace compounds of general formula (I) as hereinbefore described, which expression includes the prodrugs, the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so permits.
As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
xe2x80x9cPatientxe2x80x9d includes both human and other mammals.
xe2x80x9cAcid bioisosterexe2x80x9d means a group which has chemical and physical similarities producing broadly similar biological properties to a carboxy group (see Lipinski, Annual Reports in Medicinal Chemistry, 1986,21,p283 xe2x80x9cBioisosterism In Drug Designxe2x80x9d; Yun, Hwahak Sekyc, 1993,33,p576-579 xe2x80x9cApplication Of Bioisosterism To New Drug Designxe2x80x9d; Zhao. Huaxue Tongbao, 1995,p34-38 xe2x80x9cBioisostcric Replacement And Development Of Lead Compounds In Drug Designxe2x80x9d; Graham, Theochem, 1995,343,p105-109 xe2x80x9cTheoretical Studies Apphed To Drug Design:ab initio Electronic Distributions In Bioisosteresxe2x80x9d). Examples of suitable acid bioisosteres include: xe2x80x94C(xe2x95x90O)xe2x80x94NHOH, xe2x80x94C(xe2x95x90O)xe2x80x94CH2OH, xe2x80x94C(xe2x95x90O)xe2x80x94CH2SH, xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, heteroarylsulphonylcarbamoyl, N-methoxycarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or heterocyclic phenols such as 3-hydroxyisoxazolyl and 3-hydoxy-1-methylpyrazolyl.
xe2x80x9cAcidic functional groupxe2x80x9d means a group with an acidic hydrogen within it. The xe2x80x9ccorresponding protected derivativesxe2x80x9d are those where the acidic hydrogen atom has been replaced with a suitable protecting group. For suitable protecting groups see T. W. Greene and P. G. M. Wuts in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d John Wiley and Sons, 1991. Exemplary acidic functional groups include carboxyl (and acid bioisosteres), hydroxy, mercapto and imidazole. Exemplary protected derivatives include esters of carboxy groups, ethers of hydroxy groups, thioethers of mercapto groups and N-arylalkyl(e.g. N-benzyl) derivatives of imidazoles.
xe2x80x9cAcylxe2x80x9d means an Hxe2x80x94COxe2x80x94 or alkylxe2x80x94COxe2x80x94 group in which the alkyl group is as described herein.
xe2x80x9cAcylaminoxe2x80x9d is an acylxe2x80x94NHxe2x80x94 group wherein acyl is as defined herein.
xe2x80x9cAlkenylxe2x80x9d means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. xe2x80x9cBranchedxe2x80x9d, as used herein and throughout the text, means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear chain; here a linear alkenyl chain. xe2x80x9cLower alkenylxe2x80x9d means about 2 to about 4 carbon atoms in the chain which may be straight or branched. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.
xe2x80x9cAlkenylenexe2x80x9d means an aliphatic bivalent radical derived from a straighl or branched alkenyl group, in which the alkenyl group is as described herein. Exemplary alkenylene radicals include C2-4alkenylene radicals such as vinylene and propylene.
xe2x80x9cAlkoxyxe2x80x9d means an alkylxe2x80x94Oxe2x80x94 group in which the alkyl group is as described herein. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.
xe2x80x9cAlkoxycarbonylxe2x80x9d means an alkylxe2x80x94Oxe2x80x94COxe2x80x94 group in which the alkyl group is as described herein. Exemplary alkoxycarbonyl groups include methoxy- and ethoxycarbonyl.
xe2x80x9cAlkylxe2x80x9d means, unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 15 carbon atoms in the chain optionally substituted by one or more halogen atoms. Particular alkyl groups have from 1 to about 6 carbon atoms. xe2x80x9cLower alkylxe2x80x9d as a group or part of a lower alkoxy group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 4 carbon atoms in the chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl and dodecyl.
xe2x80x9cAlkylenexe2x80x9d means an aliphatic bivalent radical derived from a straight or branched alkyl group, in which the alkyl group is as described herein. Exemplary alkylene radicals include C1-4alkylene radicals such as methylene, ethylene and trimethylene.
xe2x80x9cAlkylsulphinylxe2x80x9d means an alkyl-SOxe2x80x94, group in which the alkyl group is as previously described. Preferred alkylsulphinyl groups are those in which the alkyl group is C1-4alkyl.
xe2x80x9cAlkylsulphonylxe2x80x9d means an alkyl-SO2xe2x80x94 group in which the alkyl group is as previously described. Preferred alkylsulphonyl groups are those in which the alkyl group is C1-4alkyl.
xe2x80x9cAlkylsulphonylcarbamoylxe2x80x9d means an alkyl-SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94 group in which the alkyl group is as previously described. Preferred alkylsulphonylcarbamoyl groups are those in which the alkyl group is C1-4alkyl.
xe2x80x9cAlkylthioxe2x80x9d means an alkyl-Sxe2x80x94 group in which the alkyl group is as previously described. Exemplary alkylthio groups include methylthio, ethylthio, isopropyltilio and lieptylthio.
xe2x80x9cAlkynylxe2x80x9d means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain.
Preferred alkynyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, i-butynyl, 3-methylbut-2-ynyl, and n-pentynyl.
xe2x80x9cAlkynylenexe2x80x9d means an aliphatic bivalent radical derived from a straight or branched alkynyl group, in which the alkynyl group is as described herein. Exemplary alkynylene radicals include C2-4alkynylene radicals such as ethynylene and propynylene.
xe2x80x9cAroylxe2x80x9d means an aryl-COxe2x80x94 group in which the aryl group is as described herein. Exemplary aroyl groups include benzoyl and 1- and 2-naphthoyl.
xe2x80x9cAroylaminoxe2x80x9d is an aroyl-NHxe2x80x94 group wherein aroyl is as previously defined.
xe2x80x9cArylxe2x80x9d as a group or part of a group denotes: (i) an optionally substituted monocyclic or multicyclic aromatic carbocyclic moiety of about 6 to about 14 carbon atoms or (ii) an optionally substituted partially saturated multicyclic aromatic carbocyclic moiety in which an aryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure such as a tetrahydronaphthyl, indenyl or indanyl ring. When R4 contains an optionally substituted aryl group, this may particularly represent optionally substituted phenyl with one or more aryl group substituents which may be the same or different, where xe2x80x9caryl group substituentxe2x80x9d includes, for example, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylsulphinyl, alkylsulphonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulphinyl, arylsulphonyl, arylthio, carboxy, cyano, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroarylamino, heteroaryloxy, hydroxy, nitro, trifluoromethyl, Y3Y4Nxe2x80x94, Y3Y4NCOxe2x80x94, Y3Y4NSO2xe2x80x94(where Y3 and Y4 are independently hydrogen, alkyl, ar and arylalkyl), Y3Y4Nxe2x80x94L3xe2x80x94Z2xe2x80x94 (where L3 is C2-6alkylene and Z2 is O, NR8 or S(O)m), alkylC(xe2x95x90O)xe2x80x94Y3Nxe2x80x94, alkylSO2xe2x80x94Y3Nxe2x80x94 or alkyl optionally substituted with aryl, heteroaryl, hydroxy, or Y3Y4Nxe2x80x94.
xe2x80x9cArylalkylxe2x80x9d means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a C1-4alkyl moiety. Exemplary arylalkyl groups include benzyl, 2-phenethyl and naphthienemethyl.
xe2x80x9cArylalkyloxyxe2x80x9d means an arylalkyl-Oxe2x80x94 group in which the arylalkyl groups is as previously described. Exemplary arylalkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.
xe2x80x9cArylalkyloxycarbonylxe2x80x9d means an arylalkyl-Oxe2x80x94COxe2x80x94 group in which the arylalkyl groups is as previously described. An exemplary arylalkyloxycarbonyl group is benzyloxycarbonyl.
xe2x80x9cArylalkylthioxe2x80x9d means an arylalkyl-Sxe2x80x94 group in which the arylalkyl group is as previously described. An exemplary arylalkylthio group is benzylthio.
xe2x80x9cArylenexe2x80x9d means an optionally substituted bivalent radical derived from an aryl group as defined above. Exemplary arylene groups include optionally substituted phenylene, naphthylene and indanylene. Suitable substituents include one or more xe2x80x9caryl group substituentsxe2x80x9d as defined above, particularly halogen, methyl or methoxy.
xe2x80x9cAryloxyxe2x80x9d means an aryl-Oxe2x80x94 group in which the aryl group is as previously described. Exemplary aryloxy groups include optionally substituted phenoxy and naphthoxy.
xe2x80x9cAryloxycarbonylxe2x80x9d means an aryl-Oxe2x80x94COxe2x80x94 group in which the aryl group is as previously described. Exemplary aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.
xe2x80x9cArylsulphinylxe2x80x9d means an aryl-SOxe2x80x94 group in which the aryl group is as previously described.
xe2x80x9cArylsulphonylxe2x80x9d means an aryl-SO2xe2x80x94 group in which the aryl group is as previously described.
xe2x80x9cArylsulphonylcarbamoylxe2x80x9d means an aryl-SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94 group in which the aryl group is as previously described.
xe2x80x9cArylthioxe2x80x9d means an aryl-Sxe2x80x94 group in which the aryl group is as previously described. Exemplary aryltliio groups include phenylthio and naphthylthio.
xe2x80x9cAzaheteroarylxe2x80x9d means an aromatic carbocyclic moiety of about 5 to about 10 ring members in which one of the ring members is nitrogen and the other ring members are chosen from carbon, oxygen, sulphur, or nitrogen. Examples of azaheteroaryl groups include pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, imidazolyl, and benzimidazolyl.
xe2x80x9cCydoalkenylxe2x80x9d means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 car bon atoms. Exemplary monocyclic cycloalkenyl rings include C3-8cycloalkenyl rings such as cyclopentenyl, cyclohexenyl or cycloheptenyl.
xe2x80x9cCycloalkylxe2x80x9d means a saturated monocyclic or bicyclic ring system of about 3 to about 10 carbon atoms optionally substituted by oxo. Exemplary monocyclic cycloalkyl rings include C3-8cycloalkyl such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.
xe2x80x9cCycloalkylalkylxe2x80x9d means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as previously described. Exemplary monocyclic cycloalkylalkyl groups include C3-8cyclo alkylC1-4alkyl groups such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.
xe2x80x9cCycloalkylenexe2x80x9d means a divalent radical derived from a cycloalkyl group as defined above. Exemplary cycloalkylene radicals include C3-8cycloalkylene radicals such as cyclopentylene and cyclohexylene.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d means fluoro, chloro, bromo, or lodo. Preferred are fluoro or chloro.
xe2x80x9cHeteroaroylxe2x80x9d means a heteroaryl-COxe2x80x94 group in which the heteroaryl group is as described herein. Exemplary groups include pyridylcarbonyl.
xe2x80x9cHeteroarylxe2x80x9d as a group or part of a group denotes: (i) an optionally substituted aromatic monocyclic or multicyclic organic moiety of about 5 to about 10 ring members in which one or more of the ring members is/are element(s) other than carbon, for example nitrogen, oxygen or sulphur (examples of such groups include benzimidazolyl, benzthriazolyl, furyl, imidazolyl a indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazoly groups, optionally substituted by one or more aryl group substituents as defined above); (ii) an optionally substituted partially saturated miulticyclic heterocarbocyclic moiety in which a heteroaryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure (examples of such groups include pyrindanyl groups). Optional substituents include one or more xe2x80x9caryl group substituentsxe2x80x9d as defined above. When L1 or R4 contains an optionally substituted heteroaryl group this may particularly represent an optionally substituted xe2x80x9cazaheteroarylxe2x80x9d group.
xe2x80x9cHeteroarylalkylxe2x80x9d means a heteroaryl-alkyl- group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a C1-4alkyl moiety such as optionally substituted pyridylC1-4alkyl (e.g. optionally substituted pyridylmethyl).
xe2x80x9cHeteroarylalkyloxyxe2x80x9d means an heteroarylalkyl-Oxe2x80x94 group in which the heteroarylalkyl group is as previously described. Preferred heteroarylalkyloxy groups include heteroarylC1 4alkyloxy such as optionally substituted pyridylC1-4alkyloxy (e.g. optionally substituted pyridylmethoxy).
xe2x80x9cHeteroarylaminoxe2x80x9d means a heteroaryl-NHxe2x80x94 group in which the heteroaryl moiety are as previously described.
xe2x80x9cHeteroaryldiylxe2x80x9d means a bivalent radical derived from a heteroaryl group as defined above.
xe2x80x9cHeteroaryloxyxe2x80x9d means an heteroaryl-Oxe2x80x94 group in which the heteroaryl group is as previously described. Exemplary heteroaryloxy groups include optionally substituted pyridyloxy. xe2x80x9cHeteroarylsulphonylckrbamoylxe2x80x9d means a heteroaryl-SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94 group in which the heteroaryl group is as previously described.
xe2x80x9cHeterocycloalkylxe2x80x9d means: (i) a cycloalkyl group of about 3 to 7 ring members in which one or more of the ring carbon atoms is replaced by O, S or NY5 (where Y5 is hydrogen, alkyl, arylalkyl, and aryl); (ii) a partially saturated bicyclic system in which an aryl or heteroaryl ring is fused to a heterocycloalkyl ring as defined in (i) above. Examples of (ii) include 1,4-benzodioxanyl, 1,3-benzodioxolyl, chromanyl, dihydrobenzofuranyl, indolinyl and dihydropyrrolopyridinyl groups).
xe2x80x9cHeterocycloalkylalkylxe2x80x9d means a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as previously described.
xe2x80x9cHeterocycloalkylenexe2x80x9d means a bivalent radical derived from a heterocycloalkyl group as defined above.
xe2x80x9cHydroxyalkylxe2x80x9d means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyl groups contain C1-4alkyl for example hydroxymethyl and 2-hydroxyethyl.
xe2x80x9cY3Y4Nxe2x80x94xe2x80x9d means a substituted or unsubstituted amino group, wherein Y3 and Y4 are as previously described. Exemplary groups include amino (H2Nxe2x80x94), methylamino, ethylmethylamino, dimethylamino and diethylamino.
xe2x80x9cY3Y4NCOxe2x80x94xe2x80x9d means a substituted or unsubstituted carbamoyl group, wherein Y3 and Y4 are as previously described. Exemplary groups are carbamoyl (H2NCOxe2x80x94) and dimethylcarbamoyl (Me2NCOxe2x80x94).
xe2x80x9cY3Y4NSO2xe2x80x94xe2x80x9d means a substituted or unsubstituted sulphamoyl group, wherein Y3 and Y4 are as previously described. Exemplary groups are sulphamoyl (H2NSO2xe2x80x94) and dimethylsulphamoyl (Me2NSO2xe2x80x94).
xe2x80x9cProdrugxe2x80x9d means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of formula (I), including N-oxides thereof. For example an ester of a compound of formula (I) containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule. Alternatively an ester of a compound of formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule.
Suitable esters of compounds of formula (I) containing a hydroxy group, are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-xcex2-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, metlianesulplionates, ethanesulphonates, benzenesulplionates, p-toluenesulphonates, cyclohexylsulphanates and quinates.
An especially useful class of esters of compounds of formula (I) containing a hydroxy group, may be formed from acid moieties selected from those described by Bundgaard et. al., J. Med. Chem., 1989, 32, page 2503-2507, and include substituted (aminomethyl)-benzoates, for example dialkylamino-methylbenzoates in which the two alkyl groups may be joined together and/or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, e.g. an alkylated nitrogen atom, more especially (morpholino-methyl)benzoates, e.g. 3- or 4-(morpholinomethyl)-benzoates, and (4-alkylpiperazin-1-yl)benzoates, e.g. 3- or 4-(4-alkylpiperazin-1-yl) benzoates.
Where the compound of the invention contains a carboxy group, or a sufficiently acidic bioisostere, base addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free acid form. The bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the cations. Pharmaceutically acceptable salts, including those derived from alkali and alkaline earth metal salts, within the scope of the invention include those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, and the like.
Some of the compounds of the present invention are basic, and such compounds are useful in the form of the free base or in the form of a pharmaceutically acceptable acid addition salt thereof.
Acid addition salts are a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form. The acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the anions. Although pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures. Pharmaceutically acceptable salts within the scope of the invention include those derived from mineral acids and organic acids, and include hydrohalides, e.g. hydrochlorides and hydrobromides, sulphates, phosphates, nitrates, sulphamates, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methane-sulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates.
As well as being useful in themselves as active compounds, salts of compounds of the invention are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.
With reference to formula (I) above, the following are particular and preferred groupings:
R1 may particularly represent hydrogen, especially when X1 represents C-R2 where R2 is lower alkyl or lower alkoxy.
X1 may particularly represent CR2, especially where R2 is C1-4alkyl (e.g. methyl) or C1-4alkoxy (e.g. methoxy).
X2 may particularly represent CR2, especially where R2 is C1-4alkyl (e.g. methyl) or C1-4alkoxy (e.g. methoxy).
X3 may particularly represent CR2 and is preferably CH.
X6 may particularly represent CR2 and is preferably CH.
One of X4 and X5 may particularly represent CR3 and the other represents CR2, especially CH.
Within R3 the moiety L1 may particularly represent a xe2x80x94R9xe2x80x94R10xe2x80x94 linkage where R9 represents a straight or branched C1-6alkylene chain, especially a straight C1-4alkylene chain such as methylene or ethylene, and R10 represents xe2x80x94C(xe2x95x90Z)xe2x80x94NR11xe2x80x94, preferably xe2x80x94C(xe2x95x90O)xe2x80x94NR11xe2x80x94 especially where R11 is:
(i) hydrogen;
(ii) C1-6alkyl (e.g. C1-4alkyl groups such as ethyl, propyl or especially methyl);
(iii) C1-6alkyl (especially C1-3alkyl) substituted by R5, where R5 is aryl (e.g. phenyl);
(iv) C1-6alkyl (especially C1-3alkyl) substituted by R5, where R5 is heteroaryl (exemplary heteroaryl groups include indolyl, imidazolyl, pyridyl and furyl);
(v) C1-6alkyl (especially C1-3alkyl) substituted by R5, where R5 is cycloalkyl (e.g. C3-8cycloalkyl such as cyclopentyl and cyclohexyl);
(vi) C1-6alkyl (especially C1-3alkyl) substituted by R5, where R5 is carboxy (or an acid bioisostere); or
(vii) C1-6alkyl (e.g. C1-4alkyl such as ethyl or propyl) substituted by R5, where R5 is xe2x80x94NY1Y2 (exemplary xe2x80x94NY1Y2 groups include acylamino, aryl(alkyl)amino, N-pyrrolidinyl and 2-oxo-N-pyrrolidinyl).
Within R3 the moiety R4 may particularly represent straight or branched C1-10alkyl (e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, n-pentyl, i-pentyl, n-hexyl, n-heptyl, n-octyl, 1,5-dimethylhexyl, n-nonyl or n-decyl).
Within R3 the moiety R4 may also particularly represent straight or branched C1-6alkyl (e.g. methyl, ethyl, n-propyl, i-propyl or n-butyl) substituted by R5, where R5 is aryl. Exemplary aryl groups include phenyl optionally substituted by one or more xe2x80x9caryl group substituentsxe2x80x9d, for example alkoxyphenyl, dialkoxyphenyl, arylalkyloxy(alkoxy)phenyl, halophenyl, dialkylaminophenyl, trifluoromethylphenyl and metlianesulphonylphenyl. R4 is preferably straight or branched C1-3alkyl substituted by diC1-3alkoxyphenyl and is particularly 3,4-diC1-3alkoxybenzyl.
Within R3 the moiety R4 may also particularly represent straight or branched C1-6alkyl (e.g. methyl, ethyl, n-propyl, i-propyl or n-butyl) substituted by R5, where R5 is heteroaryl. Exemplary heteroaryl groups include indolyl, imidazolyl, pyridyl and furyl. R4 is preferably straight or branched C1-3alkyl substituted by azaheteroaryl and is particularly 3-(imidazol-1-yl)-C1-3alkyl).
Within R3 the moiety R4 may also particularly represent straight or branched C1-6alkyl (e.g. methyl, ethyl, n-propyl, i-propyl or n-butyl) substituted by R5, where R5 is C3-8cycloalkyl. R4 is preferably straight or branched C1-3alkyl substituted by C5-6cycloalkyl.
Within R3 the moiety R4 may also particularly represent straight or branched C1-6alkyl (e.g. methyl, ethyl, n-propyl, i-propyl or n-butyl) substituted by R5, where R5 is C1-6alkoxy, especially C1-4alkoxy such as methoxy.
Within R3 the moiety R4 may also particularly represent straight or branched C1-6alkyl (e.g. methyl, ethyl, n-propyl, i-propyl or n-butyl) substituted by R5, where R5 is halo.
Within R3 the moiety R4 may also particularly represent straight or branched C1-6alkyl (e.g. methyl, ethyl, n-propyl, i-propyl or n-butyl) substituted by R5, where R5 is an acidic functional group. R4 is preferably straight or branched C1-3alkyl substituted by carboxy.
Within R3 the moiety R4 may also particularly represent straight or branched C1-6alkyl (e.g. methyl, ethyl, n-propyl, i-propyl or n-butyl) substituted by R5, where R5 is heterocycloalkyl. Exemplary heterocycloalkyl groups include benzodioxolyl and benzodioxanyl. R4 is preferably straight or branched C1-3alkyl substituted by benzodioxolyl and benzodioxanyl.
Within R3 the moiety R4 may also particularly represent straight or branched C1-6alkyl (e.g. methyl, ethyl, n-propyl, i-propyl or n-butyl) substituted by xe2x80x94NY1Y2. Exemplary xe2x80x94NY1Y2 groups include acyl,amino, aryl(alkylamino) and xe2x80x94NY1Y2 groups derived from 5-7 membered cyclic amines such as morpholine, piperidine, pyrrolidine and 2-oxo-pyrrolidine. R4 is preferably straight or branched C2-3alkyl substituted by an N-linked 5-7 membered cyclic amine, especially 3-(2-oxo-pyrrolidin-1-yl)-C2-3alkyl.
Within R3 the moiety R4 may also particularly represent C1-4alkenyl (e.g. allyl).
Within R3 the moiety n may particularly represent the integer 1 to 3, especially 1.
Within R3 the moiety Y may particularly represent carboxy or an acid bioisostere, especially carboxy.
It is to be understood that this invention covers all appropriate combinations of the particular and preferred groupings referred to herein.
A particular group of compounds of the invention are compounds of formula (Ia): 
in which R4, R9, R11 and Y are as hereinbefore defined, X1 and X2 each independently represent CR2 (wherein each R2 group is as hereinbefore defined), and xe2x80x94R9xe2x80x94CON(R11)xe2x80x94CH2xe2x80x94CON(R4)xe2x80x94CH2xe2x80x94CH2-Y is attached at the ring 3 or 4 position, and their prodrugs and pharmaceutically acceptable salts, and solvates (e.g. hydrates) of compounds of formula (Ia) and their prodrugs. Compounds of formula (Ia) in which R4 represents straight or branched C1-10alkyl (e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, n-pentyl, i-pentyl, n-hexyl, n-heptyl, n-octyl, 1,5-dimethylhexyl, n-nonyl, or n-decyl) are preferred.
Compounds of formula (Ia) in which R4 represents straight or branched C1-6alkyl (e.g. methyl, ethyl, n-propyl, i-propyl or n-butyl) substituted by R5, where R5 is aryl are also preferred. Exemplary aryl groups include phenyl optionally substituted by one or more xe2x80x9caryl group substituentsxe2x80x9d, for example alkoxyphenyl, dialkoxyphenyl, arylalkyloxy(akoxy)phenyl, halophenyl, dialkylaminophenyl, trifluoromethyl and methanesulphonylphenyl. Compounds of formula (Ia) in which R4 represents straight or branched C1-3alkyl substituted by diC1-3alkoxyphenyl, particularly 3,4-diC1-3alkoxybenzyl (e.g. 3,4-dimethoxybenzyl 3,4-diethoxybenzyl and 3-ethoxy-4-methoxybenzyl), are especially preferred.
Compounds of formula (Ia) in which R4 represents straight or branched C1-6alkyl (e.g. methyl, ethyl, n-propyl, i-propyl or n-butyl) substituted by R5, where R5 is heteroaryl are also preferred. Exemplary heteroaryl groups include indolyl, imidazolyl, pyridyl and furyl. Compounds of formula (Ia) in which R4 represents straight or branched C1-3alkyl substituted by azaheteroaryl, particularly 3-(imidazol-1-yl)-C1-3alkyl (e.g. 3-(imidazol-1-yl)-propyl), are especially preferred.
Compounds of formula (Ia) in which R4 represents straight or branched C1-6alkyl (e.g. methyl, ethyl, n-propyl, i-propyl or n-butyl) substituted by R5, where R5 is C3-8cycloalkyl are also preferred. Compounds of formula (Ia) in which R4 represents straight or branched C1-3alkyl substituted by C5-6cycloalkyl groups are especially preferred.
Compounds of formula (Ia) in which R4 represents straight or branched C1-6alkyl (e.g. methyl, ethyl, n-propyl, i-propyl or n-butyl) substituted by R5, where R5 is C1-6alkoxy, especially C1-4alkoxy (e.g. methoxy), are also preferred.
Compounds of formula (Ia) in which R4 represents straight or branched C1-6alkyl (e.g. methyl, ethyl, n-propyl, i-propyl or n-butyl) substituted by R5, where R5 is halo are also preferred.
Compounds of formula (Ia) in which R4 represents straight or branched C1-6alkyl (e.g. methyl, ethyl, n-propyl, i-propyl or n-butyl) substituted by R5, where R5 is an acidic functional group are also preferred. Compounds of formula (Ia) in which R4 is straight or branched C1-3alkyl substituted by carboxy are especially preferred.
Compounds of formula (Ia) in which R4 represents straight or branched C1-6alkyl (e.g. methyl, ethyl, n-propyl, i-propyl or n-butyl) substituted by R5, where R5 is heterocycloalkyl are also preferred. Compounds of formula (Ia) in which R4 represents straight or branched C1-3alkyl substituted by benzodioxolyl and benzodioxanyl are especially preferred.
Compounds of formula (Ia) in which R4 represents straight or branched C1-6alkyl (e.g. methyl, ethyl, n-propyl, i-propyl or n-butyl) substituted by xe2x80x94NY1Y2 are also preferred. Exemplary xe2x80x94NY1Y2 groups include acylamino, aryl(alkylamino) and xe2x80x94NY1Y2 groups derived from 5-7 membered cyclic amines such as morpholine, piperidine, pyrrolidine and 2-oxo-pyrrolidine. Compounds of formula (Ia) in which R4 represents straight or branched C1-3alkyl substituted by an N-linked 5-7 membered cyclic amine, especially 3-(2-oxo-pyrrolidin-1-yl)-C1-3alkyl (e.g. 3-(2-oxo-pyrrolidin-1-yl)-propyl), are particularly preferred.
Compounds of formula (Ia) in which R4 represents C1-4alkenyl (e.g. allyl) are also preferred.
Compounds of formula (Ia) in which R9 represents a straight or branched C1-6alkylene chain, especially a straight or branched C1-4alkylene chain, more especially methylene, are preferred.
Compounds of formula (Ia) in which R11 represents hydrogen are preferred.
Compounds of formula (Ia) in which R11 represents straight or branched C1-4alkyl, particularly methyl, are also preferred.
Compounds of formula (Ia) in which R11 represents straight or branched C1-3alkyl substituted by R5, where R5 is aryl (e.g. phenyl), are also preferred. Compounds of formula (Ia) in which R11 represents straight chain C1-3alkyl substituted by phenyl are especially preferred.
Compounds of formula (Ia) in which R11 represents straight or branched C1-3alkyl substituted by R5, where R5 is heteroaryl, are also preferred. Exemplary heteroaryl groups include indolyl, imidazolyl, pyridyl and furyl. Compounds of formula (Ia) in which R11 represents straight chain C1-3alkyl substituted by azaheteroaryl (e.g. imidazolyl or pyridyl) are especially preferred.
Compounds of formula (Ia) in which R11 represents straight or branched C1-3alkyl substituted by R5, where R5 is cycloalkyl (e.g. C3-8cycloalkyl), are also preferred. Exemplary C3-8cycloalkyl groups include cyclopentyl and cyclohexyl. Compounds of formula (Ia) in which R11 represents straight chain C1-3alkyl substituted by cyclohexyl are especially preferred.
Compounds of formula (Ia) in which R11 represents straight or branched C1-3alkyl substituted by carboxy are also preferred.
Compounds of formula (Ia) in which R11 represents straight or branched C2-3alkyl (e.g. ethyl and n-propyl) substituted by xe2x80x94NY1Y2 are also preferred. Exemplary xe2x80x94NY1Y2 groups include acylamino, aryl(alkyl)amino and xe2x80x94NY1Y2 groups derived from 5-7 membered cyclic amines such as pyrrolidine and 2-oxo-pyrrolidine. Compounds of formula (Ia) in which R11 represents ethyl or propyl substituted by 3-(2-oxo-pyrrolidin-1-yl), especially 3-(2-oxo-pyrrolidin-1-yl)-propyl, are preferred.
Compounds of formula (Ia) in which X1 represents CR2 where R2 is C1-4alky or C1-4alkoxy (e.g. methyl or methoxy), especially methyl, are preferred.
Compounds of formula (Ia) in which X2 represents CR2 where R2 is hydrogen or C1-4alkoxy, especially methoxy, are also preferred.
Compounds of formula (Ia) in which Y represents carboxy are preferred.
The group xe2x80x94R9xe2x80x94C(xe2x95x90O)xe2x80x94N(R11)xe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94NR4xe2x80x94CH2xe2x80x94CH2xe2x80x94Y may preferably be attached at the ring 4 position.
A preferred group of compounds of the invention are compounds of formula (Ia) in which:xe2x80x94R4 is C1-10alkyl, C1-6alkyl substituted by aryl (especially 3,4-dimethoxyphenylC1-3alkyl), C1-6alkyl substituted by heteroaryl (especially 3-(imidazol-1-yl)-propyl), C1-6alkyl substituted by cycloalkyl (especially cyclopentyl- and cyclohexylxe2x80x94C1-3alkyl), C1-6alkyl substituted by heterocycloalkyl (especially C1-3alkyl substituted by benzodioxolyl and benzodioxanyl), C1-6alkyl substituted by C1-6alkoxy, C1-6alkyl substituted by halo, C1-6alkyl substituted by xe2x80x94NY1Y2, [especially (2-oxo-pyrrolidin-1-yl)propyl], or C1-4alkenyl (e.g. allyl); R11 represents hydrogen, C1-4alkyl (especially methyl), C1-3alkyl substituted by aryl (especially phenylC1-3alkyl), C1-3alkyl substituted by heteroaryl (especially imidazol-1-ylC1-3alkyl and pyridylC1-3alkyl), C1-3alkyl substituted by C3-8cycloalkyl (especially cyclohexylC1-3alkyl), C1-3alkyl substituted by carboxy (especially xe2x80x94(CH2)3CO2H), or C2-3alkyl substituted by xe2x80x94NY1Y2 [especially (2-oxo-pyrrolidin-1-yl)propyl]; R9 represents a straight or branched C1-4alkylene chain, (preferably methylene); X1 represents CR2 where R2 is C1-4alkyl (especially methyl); X2 represent CR2 where R2 is C1-4alkoxy (e.g. methoxy); Y represents carboxy; and the group xe2x80x94R9xe2x80x94C(xe2x95x90O)xe2x80x94N(R11)xe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94NR4xe2x80x94CH2xe2x80x94CH2xe2x80x94Y is attached at the ring 4 position; and their prodrugs, and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their prodrugs.
Particular compounds of the invention are selected from the following:
3-{[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylami no)-acetyl]-[3-(2-oxo-pyrrolidin-1-yl)-prop-1-yl]-amino}-propionic acid, Compound A;
3-{[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino-acetyl]-[3-(3-imidazol-1-yl)prop-1-yl]-amino}-propionic acid, Compound B;
3-{(3,4-dimethoxy-benzyl)-[({[3-metloxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-amino}-propionic acid. Compound C;
3-{[({[3-methoxy-4-(3-o- tolylureido)phenyl]-acetyl}-amino)-acetyl]-[3-(2-oxo-pyrrolidin-1-prop-1-yl]-amino}-propionic acid, Compound D;
3-[[2-(ethyl-m-tolyl-amino)-ethyl]-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound E;
3-[(2-acetylamino-ethyl)-({2-[3-methoxy-4-(3-o-tolyl ureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound F;
3-[(2-chloro-benzyl)-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound G;
3-[(3-methoxy-prop-1-yl)-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound H;
3-[cyclohexymethyl-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound I;
3-[(4-methoxy-benzyl)-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino-]-propionic acid, Compound J;
3-[isobutyl-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound K;
3-[({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-(1-phenyl-ethyl)-amino]-propionic acid, Compound L;
3-{({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-[4-(5H-1,2,4-[1,2,3,]thiadiazol-4-yl)-benzyl]-amino}-propionic acid, Compound M;
3-[[1-(4-fluoro-phenyl)-ethyl]-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl-amino]-propionic acid, Compound N;
3-[(2-ethoxy-benzyl)-({2-[3methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound O;
3-[({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-(2-pyridin-2-yl-ethyl)-amino]-propionic acid, Compound P;
3-[[2-(3-bromo-4-methoxy-phenyl)-ethyl]-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound Q;
3-[(3-methoxy-benzyl)-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound R;
3-[(2-methoxy-ethyl)-({2-[3-metlioxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound S;
3-[({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-(3-methyl-butyl)-amino]-propionic acid, Compound T;
3-[({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-[2-(4-phenoxy-phenyl)-ethyl]-amino}-propionic acid, Compound U;
3-[(2-benzo[1,3]dioxol-5-yl-ethyl)-({2-[3-methoxy-4-(3-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound V;
3-[butyl-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound W;
3-[[2-(3,5-dimethoxy-phenyl)-ethyl]-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound X;
3-[({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-(furan-2-y-methyl)-amino]-propionic acid, Compound Y;
3-[allyl-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl )-amino]-propionic acid, Compound Z;
3-[({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-pyridin-3-ylmethyl-amino]-propionic acid, Compound AA;
3-[(3-chloro-prop-1-yl)-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound AB;
3-[({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-(3-phenyl-prop-1-yl)-amino]-propionic acid, Compound AC;
3-[(2-methoxyl-benzyl)-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound AD;
3-[({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-(2-morpholin-4yl-ethyl)-amino]-propionic acid, Compound AE;
3-[(4-methanesulfonyl-benzyl)-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]propionic acid, Compound AF;
3-[({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-methyl-amino]-propionic acid, Compound AG;
3-{({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-[2-(naphthalene-2-ylamino)-ethyl]-amino}-propionic acid, Compound AH;
3-[[2-(2,3-dimethoxy-phenyl)-ethyl]-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound AI;
3-[(2-diethylamino-ethyl)-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound AJ;
3[(1,5-dimethyl-hexyl)-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound AK.
3-[({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-pentyl-amino]-propionic acid, Compound AL;
3-[({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-octyl-amino]-propionic acid, Compound AM;
3-[[2-(2h-indol-3-yl)-ethyl]-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound AN;
3-[(2,3-dimethoxy-benzyl)-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound AO;
3-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-prop-1-yl-amino]-propionic acid, Compound AP;
3-[(3,3-diphenyl-prop-1-yl)-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound AQ;
3-[(2,2-diphenyl-ethyl)-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound AR;
3-[[2-(5-methoxy-2h-indol-3-yl)-ethyl]-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound AS;
3-[({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-(4-phenyl-butyl)-amino]-propionic acid, Compound AT;
3-[hexyl-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound AU;
3-[benzo[1,3]dioxol-5-ylmethyl-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound AV;
3-[(2-acetylamino-ethyl)-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound AW;
3-{({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-[2-(4-nitro-phenyl)-ethyl]-amino}-propionic acid, Compound AX;
3-[({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-(2-oxo-azepan-3-yl)-amino]-propionic acid, Compound AY;
3-[(3,5-dimethoxy-benzyl)-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound AZ;
3-[(3-dimethylamino-prop-1-yl)-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound BA;
3-[({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-naphthalen-1-ylmethyl-amino]-propionic acid, Compound BB;
3-[(1-cyclohexyl-ethyl)-({2-[3-methoxy-4-(3o-tolylureido)phenyl]-acetylamino}-acetyl)amino]-propionic acid, Compound BC;
3-[N-(3,4-dimethoxybenzyl)-2-{2-[3-methoxy-4-(3-o-tolylureido)phenyl]acetylamino}acetamido]-propionic acid, alternative name: 3-[(3,4-dimethoxy-benzyl)-({2-[3-methoxy-4-(3-o-tolylureido)-phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound BD;
3-[(2-diethylamino-ethyl)-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound BE;
3-[({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-(4-nitro-benzyl)-amino]-propionic acid, Compound BF;
3-[({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-(2-piperidin-1-yl-ethyl)-amino]-propionic acid, Compound BG;
3-[benzyl-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound BH;
3-[cyclohexyl-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound BI;
3-[isobutyl-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound BJ;
3{(3-imidazol-1-yl-prop-1-yl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-amino}-propionic acid, Compound BK;
3-[({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-(4-trifluoromethyl-benzyl)-amino]-propionic acid, Compound BL;
3-{({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-[2-(7-methyl-2h-indol-3-yl)-ethyl]-amino}-propionic acid, Compound BN;
3-[(4-dimethylamino-benzyl)-({2-[3-methoxy-4(3-o-tolylureido)phenyl]-acetylamino}acetyl)-amino]-propionic acid, Compound BO;
3-[isopropyl-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound BP;
3-[(6-chloro-2-phenoxy-phenylmethyl)-({2-[3-methoxy-4-(3o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound BQ;
3-[({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-phenethyl-amino]-propionic acid, Compound BR;
3-[({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-(1-methyl-2-phenoxy-ethyl)-amino]-propionic acid, Compound BS;
3-[[2-(5-methoxy-2H-indol-3-yl)-ethyl]-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound BT;
3-[({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-(3-phenyl-prop-1-yl)-amino]-propionic acid, Compound BU;
3-{[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-prop-1-ylamino)-acetyl]-[3-(2-oxo-pyrrolidin-1-yl)-prop-1-yl]-amino}-propionic acid, Compound BV; Compounds BW to KV;
3-{[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-(3-carboxy-prop-1-yl)-amino}-propionic acid; Compound KW;
3-{[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-[2-(2-oxo-pyrrolidin-1-yl)-ethyl]-amino}-propionic acid; Compound KX;
3-{[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-(3-carboxy-prop-1-yl)-amino}-propionic acid; Compound LA;
3-{[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-[2-(2-oxo-pyrrolidin-1-yl)-ethyl]-amino}-propionic acid; Compound LB;
3-{[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-(2-carboxy-ethyl)-amino)}-propionic acid; Compound LC;
3-{(2,3-dimethoxy-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-amino}-propionic acid; Compound AO;
3-{[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-phenyl-amino}-propionic acid; Compound LD;
3-{(3-ethoxy-4-methoxy-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-amino}-propionic acid; Compound LE;
3-{(3,4-diethoxy-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-amino}-propionic acid; Compound LF;
3-{(4-benzyloxy-3-methoxy -benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-amino}-propionic acid; Compound LG;
3-{[(1,4-benzodioxan-6-yl)-methyl]-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-amino}-propionic acid; Compound LH;
3-{[({[3-metloxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-(3-methanesulphonylamino-prop-1-yl)-amino}-propionic acid; Compound LI;
3-[(4-dimethylamino-benzyl)-[{2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-N-methylantino]-propionic acid;
3-{(3-nitro-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]acetyl}-amino)-acetyl]-amino}-propionic acid, Compound LJ;
3-{(2-thienylmethyl)-({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl)-amino}-propionic acid, Compound LK;
3-{(2-methoxy-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-amino}-propionic acid; Compound LL;
3-{(4-methyl-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-amino}-propionic acid, Compound LM;
3-{(3,4-methylenedioxy-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-amino}-propionic acid, Compound LN;
3-{(3,5-dimethoxy-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-amino}-propionic acid, Compound LO;
3-{(2-pyridylmethyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-amino}-propionic acid, Compound LP;
3-{(2-furanyimethyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-amino}-propionic acid, Compound LQ;
3-{(2-ethoxy-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]acetyl}-N-methylamino)-acetyl]-amino}-propionic acid, Compound LR;
3-{(2-thienylmethyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-amino}-propionic acid, Compound LS;
3-{(4-pyridylmethyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-amino}-propionic acid, Compound LT;
3-{(2-pyridylmethyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-amino}-propionic acid, Compound LU;
3-{(3-nitro-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-amino}-propionic acid, Compound LV;
3-{(3-pyridylmethyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-amino}-propionic acid, Compound LW;
3-{(4-[1,2,3-thiadiazol-4-yl]-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-amino}-propionic acid, Compound LX;
3-{(4-pyridylmethyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-amino}-propionic acid, Compound LY;
3-{(benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-amino}-propionic acid, Compound LZ;
3-{(2-bromo-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-amino}-propionic acid, Compound MA;
3-{(2-bromo-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-amino}-propionic acid, Compound MB;
3-{(2-chloro-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-amino}-propionic acid, Compound MC;
3-{(4-methanesulphonyl-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-amino}-propionic acid, Compound MD;
and their prodrugs, and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their prodrugs.
Preferred compounds of the invention include:
3-{[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-[3-(2-oxo-pyrrolidin-1-yl)-prop-1-yl]-amino}-propionic acid, Compound A;
3-{[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-[3-(3-imidazol-1-yl)-prop-1-yl]-amino}-propionic acid, Compound B;
3-{(3,4-dimethoxy-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-amino}-propionic acid, Compound C;
3-{[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-[3-(2-oxo-pyrrolidin-1-yl-prop-1-yl]-amino}-propionic acid, Compound D;
3-[allyl-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound Z;
3-[({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-(3-phenyl-prop-1-yl)-amino]-propionic acid, Compound AC;
3-[(2,3-dimethoxy-benzyl)-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound AO;
3-[({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-(4phenyl-butyl)-amino]-propionic acid, Compound AT;
3-[N-(3,4-dimethoxybenzyl)-2-{2-[3-methoxy-4-(3-o-tolylureido)phenyl]acetylamino}acetamido]-propionic acid, Compound BD;
3{(3-imidazol-1-yl-prop-1-yl)--[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-amino}-propionic acid, Compound BK;
3-[(4-dimethylamino-benzyl)-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound BO;
3-{[({[3-metlioxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-(3-carboxy-prop-1-yl)-amino}-propionic acid; Compound KW;
3-{[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-[2-(2-oxo-pyrrolidin-1-yl)-ethyl-amino}-propionic acid; Compound KX;
3-{(3,4-dimethoxy-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-amino}-propionic acid; Compound KY;
3-{[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-(3-carboxy-prop-1-yl)-amino}-propionic acid; Compound LA;
3-{[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-(2-carboxy-ethyl)-amino}-propionic acid; Compound LC;
3-{[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-phenyl-amino}-propionic acid; Compound LD;
3-{(3-ethoxy-4-methoxy-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-amino}-propionic acid; Compound LE;
3-{(3,4-diethoxy-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-amino}-propionic acid; Compound LF;
3-{(4-benzyloxy-3-methoxy-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-amino}-propionic acid; Compound LG;
3-{[(1,4-benzodioxan-6-yl)-methyl]-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-amino}-propionic acid; Compound LH;
3-{[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-(3-methanesulphonylamino-prop-1-yl)-amino-propionic acid; Compound LI;
3-{(3-nitro-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-amino}-propionic acid, Compound LJ;
3-{(2-thienylmethyl)-({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino}-acetyl)-amino}-propionic acid, Compound LK;
3-{(2-methoxy-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-amino}-propionic acid; Compound LL;
3-{(4-methyl-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-amino}-propionic acid, Compound LM;
3-{(3,4-methylenedioxy-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-amino}-propionic acid, Compound LN;
3-{(3,5-dimethoxy-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-amino}-propionic acid, Compound LO;
3-{(2-pyridylmethyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}amino)-acetyl]-amino}-propionic acid, Compound LP;
3-{(2-furanylmethyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-amino}-propionic acid, Compound LQ;
3-{(2-ethoxy-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-amino}-propionic acid, Compound LR;
3-{(2-thienylmethyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-amino}-propionic acid, Compound LS;
3-{(4-pyridylmethyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-amino}-propionic acid, Compound LT;
and their prodrugs, and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their prodrugs.
Especially preferred compounds of the invention include:
3-{[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-[3-(2-oxo-pyrrolidin-1-yl)-prop-1-yl]-amino}-propionic acid, Compound A;
3-{(3,4-dimethoxy-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-amino}-propionic acid, Compound C;
3-{[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-[3-(2-oxo-pyrrolidin-1-yl)-prop-1-yl]-amino}-propionic acid, Compound D;
3-[(2,3-dimethoxy-benzyl)-({2-[3-methoxy-4-(3-o-tolylureido)phenyl]-acetylamino}-acetyl)-amino]-propionic acid, Compound AO;
3-[N-(3,4-dimethoxybenzyl)-2-{2-[3-methoxy-4-(3-o-tolylureido)phenyl]acetylamino}acetamido]-propionic acid, Compound BD;
3-{[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-(3-carboxy-prop-1-yl)-amino}-propionic acid; Compound KW;
3-{(3-ethoxy-4-methoxy-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}amino)-acetyl]-amino}-propionic acid; Compound LE;
3-{(3,4-diethoxy-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-amino)-acetyl]-amino}-propionic acid; Compound LF;
and their prodrugs, and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their prodrugs.
The compounds of the invention exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. The present invention thus provides, according to a further aspect, compounds of the invention and compositions containing compounds of the invention for use in therapy.
Compounds within the scope of the present invention block the interaction of the ligand VCAM-1 to its integrin receptor VLA-4 (xcex14xcex21) according to tests described in the literature and described in vitro and in vivo procedures hereinafter, and which tests results are believed to correlate to pharmacological activity in humans and other mammals. Thus, in a further embodiment, the present invention provides compounds of the invention and compositions containing compounds of the invention for use in the treatment of a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of xcex14xcex21 mediated cell adhesion. For example, compounds of the present invention are useful in the treatment of inflammatory diseases, for example joint inflammation, including arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis and osteoarthritis. Additionally, the compounds are useful in the treatment of acute synovitis, autoimmune diabetes, autoimmune encephalomyelitis, collitis, a therosclerosis, peripheral vascular disease, cardiovascular disease, multiple sclerosis, asthma, psoriasis restenosis, myocarditis, inflammatory bowel disease and melanoma cell division in metastasis.
A special embodiment of the therapeutic methods of the present invention is the treating of asthma.
Another special embodiment of the therapeutic methods of the present invention is the treating of joint inflammation.
Another special embodiment of the therapeutic methods of the present invention is the treating of inflammatory bowel disease.
According to a further feature of the invention there is provided a method for the treatment of a human or animal patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibit or of the interaction of the ligand VCAM-1 to its integrin receptor VLA-4 (xcex14xcex21), for example conditions as hereinbefore described, which comprises (the administration to the patient of an effective amount of compound of the invention or a composition containing a compound of the invention. xe2x80x9cEffective amountxe2x80x9d is meant to describe an amount of compound of the present invention effective in inhibiting the interaction of the ligand VCAM-1 to its integrin receptor VLA-4 (xcex14xcex21), and thus producing the desired therapeutic effect.
References herein to treatment should be understood to include prophylactic therapy as well as treatment of established conditions.
The present invention also includes within its scope pharmaceutical compositions comprising at least one of the compounds of the invention in association with a pharmaceutically acceptable carrier or excipient.
Compounds of the invention may be administered by any suitable means. In practice compounds of the present invention may generally be administered parenterally, topically, rectally, orally or by inhalation, especially by the oral route.
Compositions according to the invention may be prepared according to the customary methods, using one or more pharmaceutically acceptable adjuvants or excipients. The adjuvants comprise, inter alia, diluents, sterile aqueous media and the various non-toxic organic solvents. The compositions may be presented in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and can contain one or more agents chosen from the group comprising sweeteners, flavourings, colourings, or stabilisers in order to obtain pharmaceutically acceptable preparations. The choice of vehicle and the content of active substance in the vehicle are generally determined in accordance with the solubility and chemical properties of the active compound, the particular mode of administration and the provisions to be observed in pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as stareh, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used for preparing tablets. To prepare a capsule, it is advantageous to use lactose and high molecular weight polyethylene glycols. When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension. Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.
For parenteral administration, emulsions, suspensions or solutions of the products according to the invention in vegetable oil, for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts, are used. The solutions of the salts of the products according to the invention are especially useful for administration by intramuscular or subcutaneous injection. The aqueous solutions, also comprising solutions of the salts in pure distilled water, may be used for intravenous administration with the proviso that their pH is suitably adjusted, that they are judiciously buffered and rendered isotonic with a sufficient quantity of glucose or sodium chloride and that they are sterilised by heating, irradiation or microfiltration.
For topical administration, gels (water or alcohol based), creams or ointments containing compounds of the invention may be used. Compounds of the invention may also be incorporated in a gel or matrix base for application in a patch, which would allow a controlled release of compound through the transdermal barrier.
For administration by inhalation compounds of the invention may be dissolved or suspended in a suitable carrier for use in a nebuliser or a suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier for use in a dry powder inhaler.
Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of the invention.
The percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time. The dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient In the adult, the doses are generally from about 0.001 to about 50, preferably about 0.001 to about 5, mg/kg body weight per day by inhalation, from about 0.01 to about 100, preferably 0.1 to 70, more especially 0.5 to 10, mg/kg body weight per day by oral administration, and from about 0.001 to about 10, preferably 0.01 to 1, mg/kg body weight per day by intravenous administration. In each particular case, the doses will be determined in accordance with the factors distinctive to the subject to be treated, such as age, weight, general state of health and other characteristics which can influence the efficacy of the medicinal product.
The compounds according to the invention may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the active product may be administered orally 1 to 4 times per day. Of course, for some patients, it will be necessary to prescribe not more than one or two doses per day.
Compounds of the invention may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature, for example those described by R. C. Larock in Comprehensive Organic Transformations, VCH publishers, 1989.
In the reactions described hereinafter it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T. W. Greene and P. G. M. Wuts in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d John Wiley and Sons, 1991.
Thus, for example, compounds of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined, and where the Y moiety within one of X3, X4 and X5 is carboxy, may be prepared by hydrolysis of esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined, and where the Y moiety within one of X3, X4 and X5 is xe2x80x94CO2R12 group (in which R12 is alkyl, alkenyl or arylalkyl). The hydrolysis may conveniently be carried out by alkaline hydrolysis using a base, such as an alkali metal hydroxide, e.g. lithium hydroxide, or an alkali metal carbonate, e.g. potassium carbonate, in the presence of an aqueous/organic solvent mixture, using organic solvents such as dioxan, tetrahydrofuran or methanol, at a temperature from about ambient to about reflux. The hydrolysis of the esters may also be carried out by acid hydrolysis using an inorganic acid, such as hydrochloric acid, in the presence of an aqueous/inert organic solvent mixture, using organic solvents such as dioxan or tetrahydrofuran, at a temperature from about 50xc2x0 C. to about 80xc2x0 C.
As another example compounds or formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined, and where the Y moiety within one of X3, X4 and X5 is carboxy, may be prepared by acid catalysed removal of the tert-butyl group of tert-butyl esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined, and where the Y moiety within one of X3, X4 and X5 is xe2x80x94CO2R12 (in which R12 is xe2x80x94CO2tBu), using standard reaction conditions.
In a process A compounds of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined, and where the Y moiety within one of X3, X4 and X5 is carboxy, may be prepared by coupling of an acid (or an acid halide) with an amine to give an amide bond within R3 using standard peptide coupling procedures as described hereinafter.
As an example of process A, compounds of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined, and where the Y moiety within one of X3, X4 and X5 is carboxy, may be prepared by:
(i) treating Wang resin (4-hydroxymethylphenoxylated styrene/divinylbenzene copolymer) with acryloyl chloride, in the presence of a tertiary amine, such as diisopropylethylamine, in an inert solvent, such as dichloromethane, at a temperature at about room temperature, to give Resin A: 
xe2x80x83where 
xe2x80x83represents the polymeric core comprising polystyrene crosslinked with 1% to 2% divinylbenzene.
(ii) reaction of Resin A with amines of formula (II), wherein R4 is as defined hereinbefore, in the presence of a base, such as a tertiary organic base, for example diisopropylethylamine, in dimethylformamide an at a temperature at about room temperature, to give Resin 1, in which R4 and 
xe2x80x83are as defined hereinbefore: 
(iii) reaction of Resin 1 with compounds of formula (III) 
xe2x80x83wherein R1, X1, X2 and X6 are as hereinbefore defined, one of X7, X8 and X9 represents CR14 [in which R14 is xe2x80x94L1xe2x80x94(CH2)nxe2x80x94CO2H (in which L1 and n are as hereinbefore defined)], and the others independently represent N or CR2 (in which R2 is as hereinbefore defined), in the presence of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and diisopropylethylamine in dimethylformamide, at room temperature, to give resin 2 wherein R4, R9, n and 
xe2x80x83are as hereinbefore defined and R15 represents a monovalent radical derived from (III) in which R1, X1, X2 and X6 are as hereinbefore defined, one of X7, X8 and X9 represents CH and the others independently represent N or CR2 (in which R2 is as hereinbefore defined) by removing one of the hydrogen atoms from X7, X8 or X9: 
(iv) Resin 2 may then be treated with trifluoroacetic acid in an inert solvent such as dichioromethane and at a temperature at about room temperature.
As another example of process A, compounds of formula I, wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined, and where the L1 and Y moieties within one of X3, X4 and X5 are xe2x80x94R9xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94 (where R9 is as hereinbefore defined) and carboxy respectively, may be prepared by:
(i) treating Resin 1, wherein R4 and 
xe2x80x83are as hereinbefore defined, with a suitably protected amino-acid of formula (IV), wherein R13 is a suitable amino protecting group (such as 9-fluorenylmethoxycarbonyl, FMOC) and n is as hereinbefore defined, in the presence of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and diisopropylethylamine in dimethylformamide, at room temperature to give Resin 3, wherein R4 and 
xe2x80x83are as hereinbefore defined: 
(ii) The resulting Resin 3, may then be deprotected, for example by tetreating with piperidine in dimethylformamide, at room temperature, to give Resin 4, wherein R4, n and 
xe2x80x83are as hereinbefore defined: 
(iii) Resin 4 may then be treated with compounds of general formula (III), wherein R1, X1, X2 and X6 are as hereinbefore defined, one of X7, X8 and X9 represents CR14 [in which R14 is xe2x80x94R9xe2x80x94CO2H (where R9 is as hereinbefore defined)], and the others independently represent N or CR2 (in which R2 is as hereinbefore defined), using standard peptide coupling procedures, for example those described hereinabove, to give resin 5, wherein R4, R9, R15, n and 
xe2x80x83are as hereinbefore defined: 
(iv) Resin 5 may then be treated with trifluoroacetic acid in an inert solvent such as dichloromethane and at a temperature at about room temperature.
As another example of process A, compounds of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined, and where the L1 and Y moieties within one of X3, X4 and X5 are xe2x80x94R9xe2x80x94C(xe2x95x90O)xe2x80x94(NR11)xe2x80x94 (where R9 and R11 is as hereinbefore defined) and carboxy respectively, may be prepared by:
(i) treating Resin 1, wherein R4 and 
xe2x80x83are as hereinbefore defined, with compounds of formula (V), wherein n is as hereinbefore defined and X10 is a halogen atom, preferably bromine, using standard peptide coupling procedures, for example those described hereinabove, to give Resin 6: 
(ii) Reaction of Resin 6 with amines of formula (VI), wherein R11 is as hereinbefore defined, in an inert solvent such as dimethyl sulphoxide, and at a temperature at about 80xc2x0 C. to give Resin 7, wherein R4, R11, and 
xe2x80x83are as hereinbefore defined: 
(iii) Resin 7 may then be treated with compounds of general formula (III), wherein R1, X1, X2 and X6 are as hereinbefore defined, one of X7, X8 and X9 represents CR14 [in which R14 is xe2x80x94R9 xe2x80x94CO2H (where R9 is as hereinbefore defined)], and the others independently represent N or CR2 (in which R2 is as hereinbefore defined), using standard peptide coupling procedures, for example those described hereinabove, to give resin 8 wherein R4, R9, R11, R15 n and 
xe2x80x83are as hereinbefore defined: 
(iv) Resin 8 may then be treated with trifluoroacetic acid in an inert solvent such as dichloromethane and at a temperature at about room temperature.
Esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined and where Y moiety within one of X3, X4 and X5 is a xe2x80x94CO2R12 group (in which R12 is as hereinbefore defined), may be prepared by reaction of compounds of formula (III), wherein R1, X1, X2 and X6 are as hereinbefore defined, one of X7, X8 and X9 represents C-R14 [in which R14 is xe2x80x94L1xe2x80x94(CH2)nxe2x80x94C(xe2x95x90O)X11 (where L1 and n are as hereinbefore defined and X11 is a hydroxy group, or a halogen, preferably chlorine, atom)] and the others independently represent N or CR2 (where R2 is as hereinbefore defined), with amines of formula (VII):
R4xe2x80x94HNxe2x80x94CH2xe2x80x94CH2xe2x80x94CO2R12xe2x80x83xe2x80x83(VII)
wherein R4 and R12 are as hereinbefore defined. When X11 is a hydroxy group the reaction may be carried out using standard peptide coupling procedures as described hereinbefore. When X11 is a halogen atom the reaction may be carried out with the aid of a base, such pyridine, preferably in a solvent such as tetrahydrofuran and at a temperature at about room temperature.
According to a further process B compounds of the invention may be prepared by interconversion of other compounds of the invention.
For example compounds of formula (I) wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined, and where the Y moiety within one of X3, X4 and X5 is xe2x80x94C(xe2x95x90O)xe2x80x94NHOH, may be prepared by reaction of compounds of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined, and where the Y moiety within one of X3, X4 and X5 is carboxy, with hydroxylamine using standard peptide coupling procedures such as treatment with a carbodiimide, for example dicyclohexylcarbodiimide, in the presence of triethylamine, in an inert solvent such as dichloromethane or tetrahydrofuran and at a temperature at about room temperature. The coupling may also be carried out using 1-hiydroxybenzotriazole and 1-(3-dimethylamiinopropyl)-3-ethylcarbodiimide in dichilorometliane at room temperature. The preparation may also be carried out using an O-protected hiydroxylamine such as O-(trimethylsilyl)hydroxylamine, O-(t-butyldimethylsilyl)-hydroxylamine, or O-(tetrahydropyranyl)hydroxylamine followed by treatment with acid.
As another example of the interconversion process, compounds of formula (I) containing sulphioxide linkages may be prepared by the oxidation of corresponding compounds containing xe2x80x94Sxe2x80x94 linkages. For example, the oxidation may conveniently be carried out by means of reaction with a peroxyacid, e.g. 3-chloroperbenzoic acid, preferably in an inert solvent, e.g. dichloromethane, preferably at or near room temperature, or alternatively by means of potassium hydrogen peroxomonosulphate in a medium such as aqueous methanol, buffered to about pH5, at temperatures between about 0xc2x0 C. and room temperature. This latter method is preferred for compounds containing an acid-labile group.
As another example of the interconversion process, compounds of formula (I) containing sulphone linkages may be prepared by the oxidation of corresponding compounds containing xe2x80x94Sxe2x80x94 or sulphoxide linkages. For example, the oxidation may conveniently be carried out by means of reaction with a peroxyacid, e.g. 3-chloroperbenzoic acid, preferably in an inert solvent, e.g. dichloromethane, preferably at or near room temperature.
It will be appreciated that compounds of the present invention may contain asymmetric centres. These asymmetric centres may independently be in either the R or S configuration. It will be apparent to those skilled in the art that certain compounds of the invention may also exhibit geometrical isomerism. It is to be understood that the present invention includes individual geometrical isomers and stereoisomers and mixtures thereof, including racemic mixtures, of compounds of formula (I) hereinabove. Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallisation techniques, or they are separately prepared from the appropriate isomers of their intermediates.
According to a further feature of the invention, acid addition salts of the compounds of this invention may be prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods. For example, the acid addition salts of the compounds of this invention may be prepared either by dissolving the free base in water or aqueous alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
The acid addition salts of the compounds of this invention can be regenerated from the salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.
Compounds of this invention can be regenerated from their base addition salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their base addition salts by treatment with an acid, e.g. hydrochloric acid.
Compounds of the present invention may be conveniently prepared, or formed during the process of the invention, as solvates (e.g. hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallisation from an aqueous/organic solvent mixture, using organic solvents such as dioxan, tetrahydrofuran or methanol.
According to a further feature of the invention, base addition salts of the compounds of this invention may be prepared by reaction of the free acid with the appropriate base, by the application or adaptation of known methods. For example, the base addition salts of the compounds of this invention may be prepared either by dissolving the free acid in water or aqueous alcohol solution or other suitable solvents containing the appropriate base and isolating the salt by evaporating the solution, or by reacting the free acid and base in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
The starting materials and intermediates may be prepared by the application or adaptation of known methods, for example methods as described in the Reference Examples or their obvious chemical equivalents.
Compounds of formula (III), wherein R1, X1, X2 and X6 are as hereinbefore defined, one of X7, X8 and X9 represents C-R14 (in which R14 is as described hereinabove, or a suitably protected derivative thereof) and the others independently represent N or CR10 (where R10 is as hereinbefore defined), maybe prepared by the application or adaptation of methods described in prepared as described in the specification of International Patent Application Publication No. WO 96/22966.
Intermediates of formulae (Resin 1), (Resin 2), (Resin 3), (Resin 4), (Resin 5), (Resin 6), (Resin 7) and (Resin 8) are novel compounds and, as such, they and their processes described herein for their preparation constitute further features of the present invention.
The present invention is further Exemplified but not limited by the following illustrative Examples and Reference Examples.
In the nuclear magnetic resonance spectra (NMR) the chemical shifts are expressed in ppm relative to tetramethylsilane. Abbreviations have the following significances: s=singlet; d=doublet; t=triplet; m=multiplet; dd=doublet of doublets; b=broad.
Mass spectra (MS) were recorded on a Micromass Platform II mass spectrometer fitted with an Electrospray source and an HP1100 liquid chromatograph; using a mixture of acetonitrile and water (1:1, v/v) as the mobile phase, a flow rate of 0.3 ml/minute, an injection volume of 20 xcexcl, a run time of 2.0 minutes, a scan range of 150-850 Daltons Positive/Negative, a scan time of 2.0 seconds, an ESI voltage of 3.5 Kv, an ESI pressure of 20 n/m2 Nitrogen. Abbreviations have the following significances: w=weak.